Authored and Presented by: Niket Bubna, Ph.D

1. Confidential
Compressed Timelines for
Breakthrough Therapies:
Impact on Process
Characterization & Validation
Niket Bubna
Presented at BPI West
March 2019

2. 2
Confidential
About KBI
Biologics and Breakthrough
Accelerating PC & SD-PPQ
SDM Considerations
PC & Timeline
Conclusions
KBI Biopharma

3. 4
Durham, NC (2004)
Mammalian
• Clinical & Commercial (pre-PAI)
cGMP Manufacturing
• Analytical, Formulation, Stability & QC
• Mass Spec Core Facility
• Cell Based Assays
Boulder, CO (2014)
Microbial
• Strain Development
• Process & Analytical Development
• Clinical & Commercial (Approved)
cGMP Manufacturing
• QC, Analytical, Formulation, Stability
• Particle Characterization Core
RTP, NC (2013)
Venture Center, NC (2018)
Mammalian
• Cell Line Development
• Process & Analytical Development
• Process Characterization
• Small scale Process Validation
The Woodlands, TX (2017)
Cell Therapy
• Process and Analytical Development
• cGMP Manufacturing & Testing
• Cell Based Assays
San Diego, CA (2017)
Alliance Protein Labs
• Analytical Technologies
• Leading AUC expertise
KBI Sites
North America Locations
March 2018
Louisville, CO (2018)
Elion Labs
• Analytical Technologies
• Leading Biophysical Chara

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SelexisKBI
Selexis – Geneva, Switzerland
(2017 – an affiliate of KBI)
Best in class cell line development &
candidate selection technologies
Leuven, BE (2018)
Analytical, Formulation and QC services for
GMP & non-GMP product testing
European Locations

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Large number of biologics under development and regulatory review
Expedited drug development; rolling and priority review can be requested
Biologics & Breakthrough Designation
Ref: CDER Breakthrough Therapy Designation Requests Received by Fiscal Year (As of 31 December 2018)
Ref: The Biopharmaceutical Pipeline: Innovative Therapies in Clinical Development (July 2017)
0
20
40
60
80
100
120
140
160
2012 2013 2014 2015 2016 2017 2018
Total Requests Received Granted
Breakthrough Biopharmaceuticals

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Typically carrying out process
development and scale-up
manufacturing for >10 new
biologics each year
Several products from 2013-15
are now under commercialization
Breakthrough and Fast Track
designation products under
commercialization
New Biologics IND/IMPD
0
5
10
15
20
25
30
35
2013-14 2015 2016 2017 2018
New Products Mfg Batches
KBI Mammalian Manufacturing Plant (Durham, NC)

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• Platform-based process development
• Commercialization to focus on specific improvements like titer or yield
Biologics CMC & Timelines
FIH CMC Timeline

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• Single-use for entire cell culture manufacturing process
• Bioreactor agitation and gassing scale-up is heavily dependent on preset
factors like tip speed, P/V, kLa, volumetric gas flow
KBI Mammalian Cell Culture Manufacturing Platform
Parameter XDR-50 SUB XDR-200 SUB XDR-2000 SUB
Impeller Diameter 0.2159 m 0.2159 m 0.4191 m
Impeller Power Number 1.50 1.15 0.72
Pitched-blade Impeller 3 blades at 40° 3 blades at 40° 4 blades at 40°
Turn-down Ratio 2.2:1 5:1 5:1
Aspect Ratio 1.5:1 1.5:1 1.5:1

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• Go small-scale and high throughput route for maximum steps
• Single-use bioreactors for process development and manufacturing
• Efforts for miniaturization, especially in bioreactor systems have resulted in
several products in the market
High Throughput & Single-use Technologies for Cell Culture PD & PC

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• Test SDM during Phase I/III process development
• Carry out PC for different unit operations in parallel
• Leverage Phase I experience and FMEA RA to design PC
• Aim to complete main PC stages and key experiments for first
submission
• Consider using pilot-scale runs to qualify harvest SDM
• Use high throughput tools for experiments
• Deploy statistical analysis using JMP, Design Expert etc. where possible
• Consider MVDA for large data sets like at-scale or SDM runs
Accelerated PC & SD-PPQ Timelines: Our Approach

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• LIVCA – Carry out with commercial launch process cGMP runs
• Medium-Feed Stability Study – Define stability time points with practical use
• Raw Material Qualification – Aim to test within PC and leverage PD results
• Worst-Case Linkage (Production/Harvest with Downstream)
Accelerated PC & SD-PPQ Studies: Our Approach

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Important to test proposed scale-down model during commercial process
development to ensure success in SDMQ and PC. Cell bank and scale-
dependent parameters like agitation and gassing should be tested. Focus on
matching CPPs and cell culture process outcomes
Establishing SDM

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• Equivalence testing on SDM; comparison
with cGMP results
• Need to establish acceptable difference
between scale-down models and cGMP
• Consider to establish ‘offset’ for known
differences in factors like doubling time or
a pCQA
Establishing SDM

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• Scale-down models are established using scale-dependent parameters including agitation and
gassing, which use P/V, kLa, tip speed, vvm, etc.
• Scale-down approaches in ambr250 do not necessarily use equivalent P/V or kLa values
Establishing SDM in ambr250

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Important to mimic at-scale cellular environment to obtain a robust scale-down model
Establishing SDM in ambr250
Key parameters
pH control
DO control
Temperature control
Feed addition
Titer (g/L)

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• Impact of sampling in ambr250 is larger when compared with at-scale runs
• Adjust feeding strategy to provide nutrient levels similar to at-scale
Establishing SDM in ambr250
Key parameters
pH control
DO control
Temperature control
Feed addition

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Matching cell growth, metabolite profiles is
important to qualify SDMQ using pre-
determined criteria including CPP and pCQAs
Establishing SDM in ambr250
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
VCC(e^6cells/mL)
Time (days)
Control Avg (n=3) Control 2 Avg (n=3) Pilot-Scale 200 L (n=3)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Lactate(g/L)
Time (days)
Control Avg (n=3) Control 2 Avg (n=3) Pilot-Scale 200 L (n=3)

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Predicting CPP and pCQA Performance
DOE OFAT
cGMP
SDM
Over
feedingPlanned
Excursion
Extended
Medium
HoldTiter
Response for a CPP over production PC
test conditions
SDM within cGMP range
DOE to be analyzed for design space and
prediction model
OFAT conditions show impact of stress
factors

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Response for a glycan peak from
production PC study
SDM within cGMP range
cGMP results within BDS specification range
Reduction in %peak area correlated with
test conditions
Predicting CPP and pCQA Performance
cGMP
SDM
CP
N-glycan peak (BDS Spec)
DOE Hi Condition
Planned Excursion
Hi DO

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DOE models used to generate prediction profile across tested process range
Process control strategy update – NOR and PAR
Predicting CPP and pCQA Performance
NOR
PAR

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• Preceded by commercial process development and pilot-scale (200 L) runs
• Upstream is rate-limiting
• Downstream PC can be accelerated with equipment and resources
• Draft CSD prepared based on historical development data
• PPQ campaign performed in parallel with PC
• Control Strategy is updated post-PC
Accelerated PC and SD-PPQ Timelines

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• Process development approach and SDM establishment are important for PC success
• Implement parallel PC execution of several unit operations
• Deploy high throughput approach for maximum operations including analytical testing
PC and SD-PPQ data package to support BLA submission can be achieved in 9 months
Concluding Remarks
Meaningful PC Factors
Mix of DOE & OFAT
DOE for Interactions only
Separate Raw Material
Experiments
Use FMEA RA
Predictable SDM
Mimic at-scale environment:
pH & DO Control
Feed addition
CPP & pCQA Equivalence
Robustness
Reproducibility
Benefits of ambr250 SDM
High throughput
Accuracy
Resource Efficiency
Process monitoring
Data collection
Accelerating PC Timelines
Parallel Experiments
High Throughput
Workflow
Pre-PC Studies during PD
Leverage Ph I/II Data
Pilot-scale Runs  PC
2-3 FMEA RA

23. Confidential
Thank You
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